Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

Abstract

Purpose: The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor. Experimental Design: Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti-IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines. Results: Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642. Conclusions: These findings indicate that hepatoma cells overcome IGF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC]. (Clin Cancer Res 2009;15(17):5445-56)

Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling

“…Thus, these cell variants apparently do not show other phenotypic differences apart from being insensitive to HAb AVE1642 and represent a good experimental model to highlight molecular mechanisms of resistance to anti-IGF-1R agents. We did not observe any changes in the expression of some other growth receptors, including members of the human epidermal growth factor receptor (HER) family that were recently shown to be associated with resistance to anti-IGF-1R agents (Desbois-Mouthon et al, 2009) (Supplementary Figure 1). Thus, we analyzed the gene expression profile of resistant cells, and compared these cells with parental, sensitive cells using HG-U133 Plus 2.0 Array.…”

A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity

“…[14][15][16] The interplay of these two receptor pathways may lead to resistance by the tumor to inhibition of one receptor via compensatory upregulation/activation of the reciprocal receptor, and dual inhibition of EGFR and IGF-1R has been shown to improve anti-tumor activity and overcome resistance to therapy against a single receptor in preclinical models. [17][18][19][20][21][22][23][24] Moreover, co-expression of EGFR and IGF-1R has been reported in many human tumors, including lung, colorectal and pancreatic carcinoma, [25][26][27] supporting dual targeting of these two receptors in these indications. Clinically, EGFR inhibitors are known to be efficacious in only a subpopulation of cancer patients, and intense research for molecular predictors of clinical outcomes to EGFR targeted therapies has identified K-Ras mutation as a predictive biomarker of resistance to EGFR mAbs treatment in colorectal cancer and EGFR gene mutation or high copy number as strong indicators of response to EGFR TKIs in lung cancer.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…76 Interestingly, IGF1-R inhibition in liver cancer cells evokes an analogous EGFR-dependent mechanism that involves HER3. 77 The roles of HER3 in evolving resistance extends to chemotherapy, such as resistance of HER2-overexpressing breast cancer cells to paclitaxel 65,78 and acquisition of resistance to tamoxifen by luminal B breast cancer. 79 Signature of HER3 activation and use as a biomarker As aforementioned, HER3 is trans-activated by its dimerization partners.…”